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In adult patients with severe traumatic brain injury, does the use of norepinephrine for augmenting cerebral perfusion pressure improve neurological outcome? A systematic review
Trauma Services, The Alfred Hospital, 89 Commercial Rd, Melbourne VIC, AustraliaNational Trauma Research Institute, Level 4, 89 Commercial Rd, Melbourne 3004, VIC, Australia
Trauma Services, The Alfred Hospital, 89 Commercial Rd, Melbourne VIC, AustraliaNational Trauma Research Institute, Level 4, 89 Commercial Rd, Melbourne 3004, VIC, Australia
Trauma Services, The Alfred Hospital, 89 Commercial Rd, Melbourne VIC, AustraliaNational Trauma Research Institute, Level 4, 89 Commercial Rd, Melbourne 3004, VIC, Australia
National Trauma Research Institute, Level 4, 89 Commercial Rd, Melbourne 3004, VIC, AustraliaDepartment of Neurosurgery, The Alfred Hospital, 89 Commercial Rd, Melbourne VIC, Australia
Department of Intensive Care and Hyperbaric Medicine, The Alfred Hospital, 89 Commercial Rd, Melbourne VIC, AustraliaAustralian and New Zealand Intensive Care Research Centre, School of Public and Preventive Medicine, Monash University, 553 St Kilda Road, Melbourne VIC, Australia
Trauma Services, The Alfred Hospital, 89 Commercial Rd, Melbourne VIC, AustraliaNational Trauma Research Institute, Level 4, 89 Commercial Rd, Melbourne 3004, VIC, Australia
Norepinephrine administration to target a desired cerebral perfusion pressure is a mainstay of management in severe traumatic brain injury.
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Norepinephrine use in these patients may reduce secondary injury, however its impact on overall neurological outcomes remains unknown.
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Our systematic review of over 4800 articles revealed only two studies reporting neurological outcomes in this patient group.
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Neither study provided evidence that this therapy was beneficial for neurological outcomes, morbidity or mortality in patients with sTBI.
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No evidence exists to suggest norepinephrine targeting of cerebral perfusion pressure in this group is beneficial, requiring ongoing research.
Abstract
Background and objective
Despite multiple interventions, mortality due to severe traumatic brain injury (sTBI) within mature Trauma Systems has remained unchanged over the last decade. During this time, the use of vasoactive infusions (commonly norepinephrine) to achieve a target blood pressure and cerebral perfusion pressure (CPP) has been a mainstay of sTBI management. However, evidence suggests that norepinephrine, whilst raising blood pressure, may reduce cerebral oxygenation. This study aimed to review the available evidence that links norepinephrine augmented CPP to clinical outcomes for these patients.
Methods
A systematic review examining the evidence for norepinephrine augmented CPP in TBI patients was undertaken. Strict inclusion and exclusion criteria were developed for a dedicated literature search of multiple scientific databases. Two dedicated reviewers screened articles, whilst a third dedicated reviewer resolved conflicts.
Results
The systematic review yielded 4,809 articles, of which 1,197 duplicate articles were removed. After abstract/title screening, 45 articles underwent full text review, resulting in the identification of two articles that investigated the effect of norepinephrine administration on clinical outcomes in patients following TBI when compared to other vasopressors. Neither study found a difference in neurological outcome between the vasopressor groups. No articles measured the effect of norepinephrine compared to no vasopressor use on the clinical outcome of patients with sTBI.
Conclusions
Despite being a mainstay of pharmacological management for hypotension in patients following sTBI, there is minimal clinical evidence supporting the use of norepinephrine in targeting a CPP for either improving neurological outcomes or reducing mortality. Outcomes-based clinical trials exploring the role of brain tissue perfusion and oxygenation monitoring are required to validate any benefit.
]. In adult patients with sTBI, current clinical consensus is that maintaining adequate cerebral perfusion pressure (CPP) reduces secondary injury and improves neurological outcomes [
]. Whilst specific CPP targets remain debated, there is an understanding that providing therapy to achieve a mean arterial pressure (MAP) equal to or greater than a set pressure above the observed intracranial pressure (ICP) is required in order to achieve adequate CPP, and thus preserve cerebral blood flow (CBF) [
]. Internationally in most centers, vasopressors are used to achieve this. Norepinephrine is a widely used vasopressor in North America, Europe and Australasia. Norepinephrine, however, may have detrimental physiological sequelae for individuals with sTBI – particularly in the setting of multiple injuries. Such adverse effects observed within a healthy cohort include reduced end-organ perfusion, tissue hypoxia (including reducing cerebral oxygenation) and impaired tissue healing, having a potentially important consequences for neuronal recovery in patients with sTBI [
] and despite the routine adoption of norepinephrine administration to achieve CPP targets, evidence has emerged that suggests norepinephrine contributes to paradoxical hypoperfusion secondary to vasoconstriction in other end organs, in addition to evidence suggesting norepinephrine may contribute to cerebral vasospasm in patients following subarachnoid hemorrage [
]. Furthermore, according to most reviews into this topic, little evidence exists evaluating the effect of norepinephrine on clinical outcomes in sTBI, particularly those with multisystem trauma [
This review aimed to examine the available evidence related to norepinephrine use in sTBI and to provide a considered discussion regarding its utility. Specifically, this review aimed to answer, based on the available published data, whether norepinephrine administration for patients with sTBI affects neurological outcome (as defined by Extended Glasgow Outcome Scale, (GOSE), documented at any stage throughout study follow-up), mortality (documented at any stage throughout study follow-up) or in-hospital length of stay. A secondary and subsequent aim was to determine whether the available evidence indicated sub-group(s) of TBI patients who may benefit from norepinephrine use, and also in which sub-group(s) of patients is there no benefit and/or potential harm.
Materials and methods
Six electronic databases (Ovid Medline, Ovid Embase, OVID EBM Reviews Cochrane Central Register of Controlled Trials, Scopus, Web of Science and Proquest) were searched systematically from database inception to December 31st, 2019. An initial search for studies was conducted in Medline and Embase, and an analysis of text words and subject terms was then used by to develop the search. Subject classification systems for each database were also investigated. The final searches of all 6 electronic databases was executed using the appropriate specifications of each database.
We included only human studies, and studies published in English. We included randomised control trials, all prospective and retrospective observational studies and case series. We excluded reviews/systematic reviews and meta-analyses (non-original studies) and opinion pieces. We defined “severe” TBI as having a GCS of equal to or less than 8 or mention of “severe” traumatic brain injury in the text and included any study with severe TBI with or without other traumatic injury to maximize capture of any evidence in this group. We excluded all pediatric patients, and those with atraumatic brain injury (e.g. atraumatic subarachnoid hemorrhage). We included all patients who received norepinephrine in their acute phase of management and excluded all studies that only observed/measured endogenous norepinephrine/catecholamines.
The comprehensive search strategy used for each of the databases, and inclusion and exclusion criteria, are shown in the appendix (Appendix 1, 2).
Two reviewers (PLD, WS) independently screened the titles and abstracts of the yield to determine each article's eligibility for inclusion. Any discordance regarding eligibility was discussed and resolved through consensus, with arbitration by a third reviewer (MF), if required. The full texts of the potentially eligible articles were reviewed independently by 2 reviewers (PLD, WS) to confirm eligibility. Any discordance in selection of full texts was resolved through consensus and arbitrated by a third reviewer (MF), if required. The reference lists of all included full-text studies and any systematic reviews identified were manually screened by the reviewers.
Results
The search strategy yielded 4809 articles, of which 1197 duplicate articles were removed. 3612 articles were screened based on titles and abstract, resulting in 45 full-text articles being assessed for eligibility. Of these, 43 were excluded, mostly secondary to either investigating the wrong patient group, or wrong outcomes, resulting in the inclusion of a total of 2 articles.
Citation screening and selection were documented and summarized in a PRISMA-compliant flowchart (Fig. 1).
The articles included were two original, non-randomized studies. One was a retrospective cohort study comparing the effect of different vasopressors, whilst the other was a prospective cross-over study. Neither study concluded that norepinephrine was superior to any other treatment for improving neurological outcome, morbidity or mortality in patients with sTBI (Table 1). The first study, by Sookplung et al., is a 2011 retrospective study, examining the effect of different vasopressors on 114 patients with TBI [
]. The study compared the effect of phenylephrine, norepinephrine, dopamine, vasopressin or epinephrine on cerebral hemodynamics as well as clinical outcomes of mortality, ICU and hospital length of stay and hospital discharge GCS. This study concluded that crude in-hospital mortality was lower in phenylephrine compared to the norepinephrine group (43 vs. 67%, p = 0.04), but both ICU length of stay and hospital length of stay were longer in phenylephrine compared to the norepinephrine group (10 + 1 vs. 4 + 2 days, p = 0.02; 17 + vs. 5 + 3 days, p = 0.03). They observed no difference in hospital discharge GCS between the vasopressor groups. There were no patients who were not administered a vasopressor. It is worth noting however the patients in the norepinephrine group were older (42 vs 35 years) and had higher injury severity scores (ISS) (41 vs 35), which may impact the crude mortality observed (Table 1).
Table 1Characteristics of included studies.
Sookplung et al
Ract et al
Year
2011
2001
Study design
Retrospective cohort
Prospective cross-over
Number of patients
114 Receiving single vasopressor: 101 Receiving multiple vasopressors: 13
19
Age
Phenylephrine (PHE) group (n = 46): 35 (+/- 2 SE) Norepinephrine (NE) group (n = 31): 42 (+/- 3 SE) Dopamine (DA) group (n = 21): 48 (+/- 4 SE) Vasopressin (AVP) group (n = 3): 34 (+/- 21 SE)
Median 23 (Mean 29)
GCS eligible for inclusion
≤ 8 As assessed post resuscitation on admission
≤ 8 As assessed post resuscitation on admission
GCS on study enrolment
Median = 3 (+/- 0 SE) across all groups Taken on ICU admission
Median = 7 (3 – 8 range) Taken days 1 – 8 post injury ICU
]. The study compared cerebral hemodynamics in patients treated with dopamine compared to norepinephrine and concluded that when used to target a desired MAP, norepinephrine resulted in a lower ICP and higher CCP than dobutamine. The study reported 6-month Glasgow Outcome Scale (GOS) as a secondary outcome and concluded there was no difference in 6-month GOS based on which vasopressor was used. This study did not comment further on any clinical outcomes. There were no patients who were not administered a vasopressor (Table 1).
Discussion
Key findings
This systematic review evaluated the available evidence assessing norepinephrine administration in patients with sTBI and its effect on clinical outcomes. Out of over 4000 studies reviewed, we found only two studies in adult humans that reported clinical outcomes (neurological outcome or mortality) after norepinephrine administration. No included study concluded that norepinephrine was superior to any other treatment for improving neurological outcome, morbidity or mortality in patients with sTBI and suggests that evidence for norepinephrine administration to targeting specific CPP in this population is limited.
Relationship with other studies
There were a further 13 articles that commented on physiological effects or measurements following norepinephrine administration in patients with sTBI - but did not fulfill all inclusion criteria. Of those 13 articles, only 5 commented on clinical outcomes (and were excluded due to being incorrect study design). A 2006 Cochrane review by Forsyth et al. aimed to investigate the effect of monoamine agonists on clinical improvement in patients with sTBI, defined as neurological recovery, hospital length of stay and mortality [
]. They were unable to find any studies that met every inclusion criterion, and as such concluded that there is insufficient evidence to support the routine use of monoamine agonists in patients with TBI. Similarly, a 2008 review by Pfister et al. investigating the effect of catecholamine augmented CPP in patients with TBI found no difference in clinical outcomes, concluding that there is insufficient evidence to formulate a guideline around the use of catecholamines in patients with TBI [
]. This study found that an increase in CPP (when augmented by norepinephrine) resulted in an increase in brain tissue oxygen pressure, revealing that CPP 〈 60 mmHg demonstrated brain tissue hypoxia in 50% of patients, compared to 10% of patients with a CPP 〉 70 mmHg. Despite these physiological findings, this study did not demonstrate that norepinephrine administration had an effect on neurological or survival outcomes. This is unsurprising, given the study sample size (22 patients). However, there is data suggesting that avoiding a low brain tissue oxygen tension is beneficial, as episodes of cerebral hypoxia are strongly associated with adverse neurological outcomes [
]. The pediatric study was excluded as this was not our population of interest. The 1999 case report by Ferring et al. explored the relationship between norepinephrine augmented CPP and CBF (using transcranial doppler as a surrogate) and neurological recovery in a single patient with TBI. They found that cerebral blood flow (as measured by transcranial doppler) increased with the administration of norepinephrine. They also demonstrated neurological recovery. However, this patient received multiple other pharmacological and surgical interventions without any comparitor [
The remaining articles evaluated the effect of norepinephrine augmented CPP on a variety of physiological measures, most commonly CBF and brain tissue oxygenation. A study of 17 patients by Chieregato et al. found that norepinephrine-augmented CPP was not effective in improving CBF to injured areas of the brain as measured by xenon-CT [
]. Conversely, the researchers found that elevated CPP resulted in decreased blood flow to both the area of injury and the contralateral brain. The only circumstance where they found blood flow was improved by norepinephrine augmented CPP was when their baseline blood flow was “critically low” (11 mL/100 g/min). Two studies used Position Emission Tomography (PET) to assess the impact of norepinephrine augmented CPP on CBF in patients with TBI. Coles et al. did not find a clinically significant difference in ischemic brain volume between patients who did and did not receive norepinephrine [
]. Specifically, they found that 50% of patients with a CPP <60 mmHg demonstrated brain tissue hypoxia, compared to only 10% of patients with a CPP >70 mmHg. However, they did not demonstrate a difference in neurological outcome or mortality, as discussed above. Similarly, Johnston et al. found that in patients with TBI, norepinephrine augmented CPP increased brain tissue oxygenation and reduced oxygen extraction fraction [
Effect of cerebral perfusion pressure augmentation with dopamine and norepinephrine on global and focal brain oxygenation after traumatic brain injury.
. However, there were no significant changes in metabolism variables (glucose, lactate, pyruvate, lactate/pyruvate ratio and glycerol). Finally, an 11-patient cohort study investigated the effect of norepinephrine on cerebral oxidative metabolism, as measured by near infrared spectroscopy [
]. Preliminary data from this observational study suggested norepinephrine in this group caused increases in cerebral oxidative metabolism. However, this did not match the change in oxygen extraction fraction in brain tissue, suggesting a possible metabolic discrepancy. Again, no information on clinical outcomes was reported [
Examining the most recent international guidelines on the management of sTBI, there is currently no level I or II A (high or moderate level) evidence regarding cerebral perfusion pressure or mean arterial pressure targets [
]. Of the available literature, the strongest recommendation is that a target cerebral perfusion pressure (CPP) value for “survival and favorable outcomes” is between 60 and 70 mmHg, however this is based on level II B evidence, and cannot specify a preferred method for achieving such CPP aims (vasopressor or fluid therapy) [
. As such, the results of this review are in keeping with the current international guidelines, suggesting that there remains no unified consensus as to whether fluid or vasopressor therapy is more beneficial in improving clinical outcomes, let alone vasopressor choice, in patients with sTBI.
Study implications
Chesnut et al. in their 1993 sentinel publication linked documented episodes of systemic hypotension in those with sTBI to increased mortality and recommended that ‘…the elevation of the minimum acceptable CPP as part of the treatment of the severely head injured patient should be considered on the basis of its prophylaxis against hypotension alone’ [
Early and late systemic hypotension as a frequent and fundamental source of cerebral ischemia following severe brain injury in the traumatic coma data bank.
in: Unterberg AW Schneider G-H Lanksch WR Monitoring of cerebral blood flow and metabolism in intensive care. Springer Vienna,
Vienna1993: 121-125
]. However, this review indicates that, after a quarter of a century, there is no clear evidence to suggest that the use of norepinephrine improves neurological or survival outcomes in patients with sTBI. There is also no clear evidence that norepinephrine is superior to fluid resuscitation, or other vasopressors in improving clinical outcomes in this population. In particular, there have been substantial changes in fluid resuscitation for trauma since Chesnut et al.’s paper, with blood and blood products replacing large volume saline administration. The latter, administered in response to hypotension, may have contributed in itself to the adverse neurological outcomes described.
Our results also indicate that a number of small articles exist that demonstrate physiologically plausible benefits to norepinephrine use in patients with sTBI. However, these are typically small, observational, do not examine clinical outcomes and are often performed when norepinephrine is used in conjunction with other neuroprotective therapies.
This systematic review of over 4000 articles has important clinical and research implications. This study's findings indicate that despite the widespread use of norepinephrine for sTBI, further research evaluating its impact on clinical outcomes, including post-injury GOS scores, long-term functional outcomes as well as acute morbidity and mortality is required. It also suggests a need for studies that recruit multisystem trauma subjects with concomitant neurotrauma.
Strengths and weaknesses
This review has several strengths. It was conducted in a robust and methodologically approved manner, following the PRISMA model of systematic reviews. A dedicated research librarian supervised and standardized the search strategy, as well as searching a broad range of databases to ensure a systematic, appropriate and consistent review.
There were also several limitations of this review. This manuscript is limited by the small number of studies that met all inclusion criteria. However, this highlights the significant gap that exists in the literature despite the routine adoption of norepinephrine augmented CPP therapy in patients with sTBI. Additionally, this review focuses exclusively on administration of exogenous norepinephrine. It should also be noted however that endogenous catecholamines, including norepinephrine, become significantly elevated in severe trauma, including sTBI [
]. It is worth noting that elevated levels of circulating norepinephrine upon admission is associated with higher morbidity and mortality in sTBI, however an in-depth analysis of the effect of circulating endogenous norepinephrine goes beyond the scope of this review [
Upon systematic review of the available literature, this study found two publications of adult humans with sTBI that reported clinical outcomes after norepinephrine augmented CPP-targeted intervention. These studies did not investigate neurological recovery or overall morbidity/mortality improvement with norepinephrine compared to a baseline control. Despite being adopted internationally as standard care in patients with sTBI, there is currently a paucity of evidence to support the routine use of norepinephrine in patients with sTBI. Furthermore, the potential harms of this therapy - particularly in the setting of multi-system trauma remain unknown. Outcomes-based clinical trials - such as the recently commenced BONANZA trial exploring the role of brain tissue oxygen monitoring - are required to validate any benefit [
ACTRN12619001328167p. The BONANZA Trial -a randomised controlled trial in patients with severe traumatic brain injury that will determine whether a neuro-intensive care management strategy guided by continuous brain tissue oxygen (PbtO2) monitoring and intracranial pressure (ICP) monitoring will improve neurological and functional outcomes at 6 months measured by the GOSE, when compared to standard care using ICP monitoring alone. https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378178, 2019.
Prof. A Udy declares he is the recipient of a grant as lead-author on the BONANZArandomized control trial. This study deals with a similar research topic, however no funding from this grant was used for the purposes of this review. No other authors declare any competing interests.
Effect of cerebral perfusion pressure augmentation with dopamine and norepinephrine on global and focal brain oxygenation after traumatic brain injury.
Early and late systemic hypotension as a frequent and fundamental source of cerebral ischemia following severe brain injury in the traumatic coma data bank.
in: Unterberg AW Schneider G-H Lanksch WR Monitoring of cerebral blood flow and metabolism in intensive care. Springer Vienna,
Vienna1993: 121-125
ACTRN12619001328167p. The BONANZA Trial -a randomised controlled trial in patients with severe traumatic brain injury that will determine whether a neuro-intensive care management strategy guided by continuous brain tissue oxygen (PbtO2) monitoring and intracranial pressure (ICP) monitoring will improve neurological and functional outcomes at 6 months measured by the GOSE, when compared to standard care using ICP monitoring alone. https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378178, 2019.
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